Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance
Identifieur interne : 000A04 ( Istex/Corpus ); précédent : 000A03; suivant : 000A05Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance
Auteurs : Gunnar M. Buyse ; Gerry Van Der Mieren ; Michael Erb ; Jan D'Hooge ; Paul Herijgers ; Erik Verbeken ; Alejandro Jara ; An Van Den Bergh ; Luc Mertens ; Isabelle Courdier-Fruh ; Patrizia Barzaghi ; Thomas MeierSource :
- European Heart Journal [ 0195-668X ] ; 2009-01.
Abstract
Aims Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress. Methods and results In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusion We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.
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DOI: 10.1093/eurheartj/ehn406
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Buyse</name><affiliation><mods:affiliation>Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gunnar.buyse@uzleuven.be</mods:affiliation></affiliation></author><author><name sortKey="Van Der Mieren, Gerry" sort="Van Der Mieren, Gerry" uniqKey="Van Der Mieren G" first="Gerry" last="Van Der Mieren">Gerry Van Der Mieren</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Erb, Michael" sort="Erb, Michael" uniqKey="Erb M" first="Michael" last="Erb">Michael Erb</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="D Hooge, Jan" sort="D Hooge, Jan" uniqKey="D Hooge J" first="Jan" last="D'Hooge">Jan D'Hooge</name><affiliation><mods:affiliation>Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Herijgers, Paul" sort="Herijgers, Paul" uniqKey="Herijgers P" first="Paul" last="Herijgers">Paul Herijgers</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Verbeken, Erik" sort="Verbeken, Erik" uniqKey="Verbeken E" first="Erik" last="Verbeken">Erik Verbeken</name><affiliation><mods:affiliation>Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Jara, Alejandro" sort="Jara, Alejandro" uniqKey="Jara A" first="Alejandro" last="Jara">Alejandro Jara</name><affiliation><mods:affiliation>Biostatistical Center KU Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Van Den Bergh, An" sort="Van Den Bergh, An" uniqKey="Van Den Bergh A" first="An" last="Van Den Bergh">An Van Den Bergh</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Mertens, Luc" sort="Mertens, Luc" uniqKey="Mertens L" first="Luc" last="Mertens">Luc Mertens</name><affiliation><mods:affiliation>Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Courdier Fruh, Isabelle" sort="Courdier Fruh, Isabelle" uniqKey="Courdier Fruh I" first="Isabelle" last="Courdier-Fruh">Isabelle Courdier-Fruh</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Barzaghi, Patrizia" sort="Barzaghi, Patrizia" uniqKey="Barzaghi P" first="Patrizia" last="Barzaghi">Patrizia Barzaghi</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Meier, Thomas" sort="Meier, Thomas" uniqKey="Meier T" first="Thomas" last="Meier">Thomas Meier</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7</idno><date when="2009" year="2009">2009</date><idno type="doi">10.1093/eurheartj/ehn406</idno><idno type="url">https://api.istex.fr/document/78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">000A04</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a">Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title><author><name sortKey="Buyse, Gunnar M" sort="Buyse, Gunnar M" uniqKey="Buyse G" first="Gunnar M." last="Buyse">Gunnar M. Buyse</name><affiliation><mods:affiliation>Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gunnar.buyse@uzleuven.be</mods:affiliation></affiliation></author><author><name sortKey="Van Der Mieren, Gerry" sort="Van Der Mieren, Gerry" uniqKey="Van Der Mieren G" first="Gerry" last="Van Der Mieren">Gerry Van Der Mieren</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Erb, Michael" sort="Erb, Michael" uniqKey="Erb M" first="Michael" last="Erb">Michael Erb</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="D Hooge, Jan" sort="D Hooge, Jan" uniqKey="D Hooge J" first="Jan" last="D'Hooge">Jan D'Hooge</name><affiliation><mods:affiliation>Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Herijgers, Paul" sort="Herijgers, Paul" uniqKey="Herijgers P" first="Paul" last="Herijgers">Paul Herijgers</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Verbeken, Erik" sort="Verbeken, Erik" uniqKey="Verbeken E" first="Erik" last="Verbeken">Erik Verbeken</name><affiliation><mods:affiliation>Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Jara, Alejandro" sort="Jara, Alejandro" uniqKey="Jara A" first="Alejandro" last="Jara">Alejandro Jara</name><affiliation><mods:affiliation>Biostatistical Center KU Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Van Den Bergh, An" sort="Van Den Bergh, An" uniqKey="Van Den Bergh A" first="An" last="Van Den Bergh">An Van Den Bergh</name><affiliation><mods:affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Mertens, Luc" sort="Mertens, Luc" uniqKey="Mertens L" first="Luc" last="Mertens">Luc Mertens</name><affiliation><mods:affiliation>Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium</mods:affiliation></affiliation></author><author><name sortKey="Courdier Fruh, Isabelle" sort="Courdier Fruh, Isabelle" uniqKey="Courdier Fruh I" first="Isabelle" last="Courdier-Fruh">Isabelle Courdier-Fruh</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Barzaghi, Patrizia" sort="Barzaghi, Patrizia" uniqKey="Barzaghi P" first="Patrizia" last="Barzaghi">Patrizia Barzaghi</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author><author><name sortKey="Meier, Thomas" sort="Meier, Thomas" uniqKey="Meier T" first="Thomas" last="Meier">Thomas Meier</name><affiliation><mods:affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">European Heart Journal</title><idno type="ISSN">0195-668X</idno><idno type="eISSN">1522-9645</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-01">2009-01</date><biblScope unit="volume">30</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="116">116</biblScope><biblScope unit="page" to="124">124</biblScope></imprint><idno type="ISSN">0195-668X</idno></series><idno type="istex">78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7</idno><idno type="DOI">10.1093/eurheartj/ehn406</idno><idno type="ArticleID">ehn406</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0195-668X</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract">Aims Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress. Methods and results In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusion We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.</div></front></TEI><istex><corpusName>oup</corpusName><author><json:item><name>Gunnar M. Buyse</name><affiliations><json:string>Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium</json:string><json:string>E-mail: gunnar.buyse@uzleuven.be</json:string></affiliations></json:item><json:item><name>Gerry Van der Mieren</name><affiliations><json:string>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Michael Erb</name><affiliations><json:string>Santhera Pharmaceuticals, Liestal, Switzerland</json:string></affiliations></json:item><json:item><name>Jan D'hooge</name><affiliations><json:string>Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Paul Herijgers</name><affiliations><json:string>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Erik Verbeken</name><affiliations><json:string>Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Alejandro Jara</name><affiliations><json:string>Biostatistical Center KU Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>An Van Den Bergh</name><affiliations><json:string>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Luc Mertens</name><affiliations><json:string>Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium</json:string></affiliations></json:item><json:item><name>Isabelle Courdier-Fruh</name><affiliations><json:string>Santhera Pharmaceuticals, Liestal, Switzerland</json:string></affiliations></json:item><json:item><name>Patrizia Barzaghi</name><affiliations><json:string>Santhera Pharmaceuticals, Liestal, Switzerland</json:string></affiliations></json:item><json:item><name>Thomas Meier</name><affiliations><json:string>Santhera Pharmaceuticals, Liestal, Switzerland</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Muscular dystrophy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Therapy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Cardiomyopathy</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Hemodynamics</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Heart failure</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Animal model</value></json:item></subject><articleId><json:string>ehn406</json:string></articleId><language><json:string>eng</json:string></language><originalGenre><json:string>research-article</json:string></originalGenre><abstract>Aims Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress. Methods and results In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusion We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.</abstract><qualityIndicators><score>7.28</score><pdfVersion>1.2</pdfVersion><pdfPageSize>664.214 x 862.639 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>6</keywordCount><abstractCharCount>1346</abstractCharCount><pdfWordCount>5750</pdfWordCount><pdfCharCount>40884</pdfCharCount><pdfPageCount>9</pdfPageCount><abstractWordCount>190</abstractWordCount></qualityIndicators><title>Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title><genre><json:string>research-article</json:string></genre><host><volume>30</volume><publisherId><json:string>eurheartj</json:string></publisherId><pages><last>124</last><first>116</first></pages><issn><json:string>0195-668X</json:string></issn><issue>1</issue><genre><json:string>journal</json:string></genre><language><json:string>unknown</json:string></language><eissn><json:string>1522-9645</json:string></eissn><title>European Heart Journal</title></host><categories><wos><json:string>CARDIAC & CARDIOVASCULAR SYSTEMS</json:string></wos></categories><publicationDate>2009</publicationDate><copyrightDate>2009</copyrightDate><doi><json:string>10.1093/eurheartj/ehn406</json:string></doi><id>78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7</id><score>0.26695943</score><fulltext><json:item><original>true</original><mimetype>application/pdf</mimetype><extension>pdf</extension><uri>https://api.istex.fr/document/78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7/fulltext/pdf</uri></json:item><json:item><original>false</original><mimetype>application/zip</mimetype><extension>zip</extension><uri>https://api.istex.fr/document/78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7/fulltext/zip</uri></json:item><istex:fulltextTEI uri="https://api.istex.fr/document/78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7/fulltext/tei"><teiHeader><fileDesc><titleStmt><title level="a">Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title></titleStmt><publicationStmt><authority>ISTEX</authority><publisher>Oxford University Press</publisher><availability><p>Published on behalf of the European Society of Cardiology. All rights reserved. The Author 2008. For permissions please email: journals.permissionsoxfordjournals.org</p></availability><date>2008-09-10</date></publicationStmt><notesStmt><note>This paper was guest edited by Dr Philipp Bonhoeffer, Great Ormond Street Hospital for Children, London, UK</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a">Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title><author xml:id="author-1"><persName><forename type="first">Gunnar M.</forename><surname>Buyse</surname></persName><email>gunnar.buyse@uzleuven.be</email><affiliation>Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium</affiliation></author><author xml:id="author-2"><persName><forename type="first">Gerry</forename><surname>Van der Mieren</surname></persName><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-3"><persName><forename type="first">Michael</forename><surname>Erb</surname></persName><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation></author><author xml:id="author-4"><persName><forename type="first">Jan</forename><surname>D'hooge</surname></persName><affiliation>Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-5"><persName><forename type="first">Paul</forename><surname>Herijgers</surname></persName><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-6"><persName><forename type="first">Erik</forename><surname>Verbeken</surname></persName><affiliation>Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-7"><persName><forename type="first">Alejandro</forename><surname>Jara</surname></persName><affiliation>Biostatistical Center KU Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-8"><persName><forename type="first">An</forename><surname>Van Den Bergh</surname></persName><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-9"><persName><forename type="first">Luc</forename><surname>Mertens</surname></persName><affiliation>Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium</affiliation></author><author xml:id="author-10"><persName><forename type="first">Isabelle</forename><surname>Courdier-Fruh</surname></persName><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation></author><author xml:id="author-11"><persName><forename type="first">Patrizia</forename><surname>Barzaghi</surname></persName><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation></author><author xml:id="author-12"><persName><forename type="first">Thomas</forename><surname>Meier</surname></persName><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation></author></analytic><monogr><title level="j">European Heart Journal</title><idno type="pISSN">0195-668X</idno><idno type="eISSN">1522-9645</idno><imprint><publisher>Oxford University Press</publisher><date type="published" when="2009-01"></date><biblScope unit="volume">30</biblScope><biblScope unit="issue">1</biblScope><biblScope unit="page" from="116">116</biblScope><biblScope unit="page" to="124">124</biblScope></imprint></monogr><idno type="istex">78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7</idno><idno type="DOI">10.1093/eurheartj/ehn406</idno><idno type="ArticleID">ehn406</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2008-09-10</date></creation><langUsage><language ident="en">en</language></langUsage><abstract><p>Aims Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress. Methods and results In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusion We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.</p></abstract><textClass><keywords scheme="keyword"><list><head>Keywords</head><item><term>Muscular dystrophy</term></item><item><term>Therapy</term></item><item><term>Cardiomyopathy</term></item><item><term>Hemodynamics</term></item><item><term>Heart failure</term></item><item><term>Animal model</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2008-09-10">Created</change><change when="2009-01">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><original>false</original><mimetype>text/plain</mimetype><extension>txt</extension><uri>https://api.istex.fr/document/78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article article-type="research-article"><front><journal-meta><journal-id journal-id-type="hwp">ehj</journal-id><journal-id journal-id-type="publisher-id">eurheartj</journal-id><journal-title>European Heart Journal</journal-title><issn pub-type="ppub">0195-668X</issn><issn pub-type="epub">1522-9645</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="doi">10.1093/eurheartj/ehn406</article-id><article-id pub-id-type="publisher-id">ehn406</article-id><article-categories><subj-group subj-group-type="heading"><subject>PRECLINICAL RESEARCH</subject></subj-group></article-categories><title-group><article-title>Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient <italic>mdx</italic> mouse: cardiac protection and improved exercise performance</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Buyse</surname><given-names>Gunnar M.</given-names></name><xref ref-type="aff" rid="af1">1</xref><xref ref-type="corresp" rid="cor1">*</xref></contrib><contrib contrib-type="author"><name><surname>Van der Mieren</surname><given-names>Gerry</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Erb</surname><given-names>Michael</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>D'hooge</surname><given-names>Jan</given-names></name><xref ref-type="aff" rid="af4">4</xref></contrib><contrib contrib-type="author"><name><surname>Herijgers</surname><given-names>Paul</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Verbeken</surname><given-names>Erik</given-names></name><xref ref-type="aff" rid="af5">5</xref></contrib><contrib contrib-type="author"><name><surname>Jara</surname><given-names>Alejandro</given-names></name><xref ref-type="aff" rid="af6">6</xref></contrib><contrib contrib-type="author"><name><surname>Van Den Bergh</surname><given-names>An</given-names></name><xref ref-type="aff" rid="af2">2</xref></contrib><contrib contrib-type="author"><name><surname>Mertens</surname><given-names>Luc</given-names></name><xref ref-type="aff" rid="af7">7</xref></contrib><contrib contrib-type="author"><name><surname>Courdier-Fruh</surname><given-names>Isabelle</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Barzaghi</surname><given-names>Patrizia</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib><contrib contrib-type="author"><name><surname>Meier</surname><given-names>Thomas</given-names></name><xref ref-type="aff" rid="af3">3</xref></contrib></contrib-group><aff id="af1"><label>1</label><addr-line>Department of Pediatric Neurology</addr-line>, <institution>University Hospitals Leuven</institution>, <addr-line>Herestraat 49, B-3000 Leuven</addr-line>, <country>Belgium</country></aff><aff id="af2"><label>2</label><addr-line>Department of Experimental Cardiac Surgery</addr-line>, <institution>University Hospitals Leuven</institution>, <addr-line>Leuven</addr-line>, <country>Belgium</country></aff><aff id="af3"><label>3</label><addr-line>Santhera Pharmaceuticals, Liestal</addr-line>, <country>Switzerland</country></aff><aff id="af4"><label>4</label><addr-line>Department of Cardiovascular Imaging and Dynamics</addr-line>, <institution>University Hospitals Leuven</institution>, <addr-line>Leuven</addr-line>, <country>Belgium</country></aff><aff id="af5"><label>5</label><addr-line>Department of Morphology and Molecular Pathology</addr-line>, <institution>University Hospitals Leuven</institution>, <addr-line>Leuven</addr-line>, <country>Belgium</country></aff><aff id="af6"><label>6</label><addr-line>Biostatistical Center KU Leuven, Leuven</addr-line>, <country>Belgium</country></aff><aff id="af7"><label>7</label><addr-line>Department of Pediatric Cardiology</addr-line>, <institution>University Hospitals Leuven</institution>, <addr-line>Leuven</addr-line>, <country>Belgium</country></aff><author-notes><corresp id="cor1"><label>*</label>Corresponding author. Tel: <phone>+32 16 34 38 45</phone>, Fax: <fax>+32 16 34 38 42</fax>, Email: <email>gunnar.buyse@uzleuven.be</email></corresp><fn><p><bold>This paper was guest edited by Dr Philipp Bonhoeffer, Great Ormond Street Hospital for Children, London, UK</bold></p></fn></author-notes><pub-date pub-type="ppub"><month>1</month><year>2009</year></pub-date><pub-date pub-type="epub"><day>10</day><month>9</month><year>2008</year></pub-date><volume>30</volume><issue>1</issue><fpage>116</fpage><lpage>124</lpage><history><date date-type="received"><day>1</day><month>2</month><year>2008</year></date><date date-type="rev-recd"><day>8</day><month>8</month><year>2008</year></date><date date-type="accepted"><day>21</day><month>8</month><year>2008</year></date></history><copyright-statement>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org</copyright-statement><copyright-year>2009</copyright-year><license license-type="creative-commons" xlink:href="http://creativecommons.org/licenses/by-nc/2.0/uk/"><p>The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.</p></license><abstract><sec><title>Aims</title><p>Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the <italic>mdx</italic> mouse model of DMD, based on the drug’s potential to improve mitochondrial respiratory chain function and reduce oxidative stress.</p></sec><sec><title>Methods and results</title><p>In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in <italic>mdx</italic> and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing <italic>in vivo</italic>, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in <italic>mdx</italic> mice.</p></sec><sec><title>Conclusion</title><p>We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient <italic>mdx</italic> mouse. Our data also illustrate that the <italic>mdx</italic> mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.</p></sec></abstract><kwd-group><title>Keywords</title><kwd>Muscular dystrophy</kwd><kwd>Therapy</kwd><kwd>Cardiomyopathy</kwd><kwd>Hemodynamics</kwd><kwd>Heart failure</kwd><kwd>Animal model</kwd></kwd-group></article-meta></front></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Long-term blinded placebo-controlled study of SNT-MC17/idebenone in the dystrophin deficient mdx mouse: cardiac protection and improved exercise performance</title></titleInfo><name type="personal"><namePart type="given">Gunnar M.</namePart><namePart type="family">Buyse</namePart><affiliation>Department of Pediatric Neurology, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium</affiliation><affiliation>E-mail: gunnar.buyse@uzleuven.be</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Gerry</namePart><namePart type="family">Van der Mieren</namePart><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Michael</namePart><namePart type="family">Erb</namePart><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Jan</namePart><namePart type="family">D'hooge</namePart><affiliation>Department of Cardiovascular Imaging and Dynamics, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Paul</namePart><namePart type="family">Herijgers</namePart><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Erik</namePart><namePart type="family">Verbeken</namePart><affiliation>Department of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Alejandro</namePart><namePart type="family">Jara</namePart><affiliation>Biostatistical Center KU Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">An</namePart><namePart type="family">Van Den Bergh</namePart><affiliation>Department of Experimental Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Luc</namePart><namePart type="family">Mertens</namePart><affiliation>Department of Pediatric Cardiology, University Hospitals Leuven, Leuven, Belgium</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Isabelle</namePart><namePart type="family">Courdier-Fruh</namePart><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Patrizia</namePart><namePart type="family">Barzaghi</namePart><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Thomas</namePart><namePart type="family">Meier</namePart><affiliation>Santhera Pharmaceuticals, Liestal, Switzerland</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article"></genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2009-01</dateIssued><dateCreated encoding="w3cdtf">2008-09-10</dateCreated><copyrightDate encoding="w3cdtf">2009</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract>Aims Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drugs potential to improve mitochondrial respiratory chain function and reduce oxidative stress. Methods and results In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice. Conclusion We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.</abstract><note type="footnotes">This paper was guest edited by Dr Philipp Bonhoeffer, Great Ormond Street Hospital for Children, London, UK</note><subject><genre>Keywords</genre><topic>Muscular dystrophy</topic><topic>Therapy</topic><topic>Cardiomyopathy</topic><topic>Hemodynamics</topic><topic>Heart failure</topic><topic>Animal model</topic></subject><relatedItem type="host"><titleInfo><title>European Heart Journal</title></titleInfo><genre type="journal">journal</genre><identifier type="ISSN">0195-668X</identifier><identifier type="eISSN">1522-9645</identifier><identifier type="PublisherID">eurheartj</identifier><identifier type="PublisherID-hwp">ehj</identifier><part><date>2009</date><detail type="volume"><caption>vol.</caption><number>30</number></detail><detail type="issue"><caption>no.</caption><number>1</number></detail><extent unit="pages"><start>116</start><end>124</end></extent></part></relatedItem><identifier type="istex">78F907E922D4FBA096C9ADBB8A4BBDDFECB735C7</identifier><identifier type="DOI">10.1093/eurheartj/ehn406</identifier><identifier type="ArticleID">ehn406</identifier><accessCondition type="use and reproduction" contentType="copyright">Published on behalf of the European Society of Cardiology. 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